This project examines the neutralizing antibody responses in the acute/early phases of HIV-1 infection. The ultimate goal is to determine if neutralizing antibodies play a role in virus clearance or reduction in virus load. Based on a limited number of studies, current evidence suggests neutralizing antibodies arise too late to contribute to these early processes. We will take advantage of the Trinidad cohort to examine these questions in more detail. The results will be compared to cellular effector mechanisms and other humoral reactivities proposed for study in other sections of the program. The project will also work closely with 9002 in the isolation and preparation of cloned virus isolates and chimeric virus clones. More specifically we will follow the development of antibody responses which neutralize autologous virus isolates derived from PBMCs as well as heterologous primary and prototypic virus isolates. We will concentrate these efforts on virus and sera obtained in the earliest phases of infection and also continue the analysis through the first several years post sero-conversion. We will also examine other aspects of the humoral immune response including antibody binding to envelope components that may represent targets of neutralizing antibody as well as antibodies that block binding of virus to CD4. In those cases in which autologous neutralization is apparent we will define serologic and/or virologic determinants involved. There remain serious questions about the validity of assays currently utilized to detect neutralization of primary isolates. Rules that govern neutralization of laboratory adapted virus isolates do not apply to primary isolates which seriously impacts on the interpretation of the results that will be obtained in this project. Therefore, an important component of our studies will be developmental efforts aimed at a better understanding of experimental variables that affect antibody neutralization. These will address the artificially activated PBMCs required for growth of most primary isolates and the genomic complexity of the virus preparations.